Friedreich ataxia (FRDA) is the most common hereditary ataxia, with an estimated prevalence of 1 in 50,000 and a deduced carrier frequency of 1/120 in the European population. FRDA is an autosomal recessive degenerative disease characterized by progressive gait and limb ataxia, a lack of tendon reflexes in the legs, loss of position sense, dysarthria, and pyramidal weakness of the legs. Hypertrophic cardiomyopathy is found in almost all patients. Diabetes mellitus is seen in about 10% of the cases, carbohydrate intolerance in an additional 20%, and a reduced insulin response to arginine stimulation in all cases. The age of onset is usually around puberty, and almost always before age twenty-five. Most patients are wheelchair bound by their late twenties and currently there is no treatment to slow progression of the disease.
The first pathologic changes are thought to occur in the dorsal root ganglia with loss of large sensory neurons, followed by deterioration of the sensory posterior columns, spinocerebellar tracts and corticospinal motor tracts of the spinal cord, and atrophy of large sensory fibers in peripheral nerves. Only occasional mild degenerative changes are seen in the cerebellum, pons and medulla. While most symptoms are a consequence of neuronal degeneration, cardiomyopathy and diabetes are thought to reflect independent sites of primary degeneration. Overall, the pathology of FRDA is very different from that of other hereditary ataxias, particularly the dominant forms and ataxia-telangiectasia, where the cerebellum is the primary site of degeneration.
The mutated gene in FRDA has been mapped to chromosome 9q13-q21.1, S. Chamberlain, et al., Nature, 334:248 (1988); and the FRDA candidate region has been narrowed to a 150 kb segment flanked by the Z0-2 gene (distal) and the marker F8101 (proximal), L. Montermini et al., Am. J. Hum. Genet., 57:1061 (1995). Previously proposed candidate genes are excluded: the X104/CSFA1/Z0-2 gene on the basis of the absence of deleterious mutation in patients, and the STM7 and PRKACG genes because they lie in entirety on the centromeric side of F8101 (FIG. 1A).